As mental disorders, schizophrenia, bipolar emotional disorder, recurrent depressive disorder, phobic anxiety disorder, and the like are known (Non-Patent Document 1). Currently, antipsychotic drugs, antidepressant drugs, antianxiety drugs and the like have been used clinically to treat these mental disorders. There is a need, however, for a drug with increased efficacy and fewer adverse drug reactions.
For example, many of the antipsychotic drugs are dopamine receptor blockers, and may induce extrapyramidal symptoms. Besides, the effect of these drugs to improve negative symptoms is insufficient. It is known for antidepressant drugs that about several weeks are required to manifest their therapeutic effect, some patients are resistant to their therapy, and the remission rate after their therapy is 50% or less. Many antidepressant drugs are known to be addictive and have adverse effects such as drowsiness.
On the other hand, a decreased local brain volume has been reported in various pathological conditions, such as depression, schizophrenia, and mood disorder. A decreased number of brain neurons observed in mental disorders is thought to be closely associated with these pathological conditions of these diseases (Non-Patent Documents 2-5).
Recently, it has been revealed that neurons are generated through proliferation and differentiation of neural stem cells and neural progenitor cells existing in the adult brain (Non-Patent Document 6), and the possibility is indicated that activation and differentiation of endogenous neural stem cells and/or neural progenitor cells will reconstruct the nerve tissue and function reduced in various disorders.
Furthermore, based on the fact that antidepressant drugs, antipsychotic drugs and the like actually exhibit a neurogenesis inducing effect, it is indicated that focusing on the neurogenesis inducing effect will lead to the development of more effective mental disorder therapeutic agents (Non-Patent Documents 7 and 8).
Compounds that induce proliferation and differentiation of the neural stem cells and/or the neural progenitor cells are considered useful as mental disorder therapeutic agents due to their effect of reconstructing the nerve tissue and function reduced in various disorders (Patent Document 2).
To date, alkyl ether derivatives have been reported to have effects of neuroprotection, nerve regeneration, and neurite outgrowth promotion (Patent Document 1). However, their neurogenesis inducing effect has not been known at all.
Patent Document 1: WO 03/035647 pamphlet
Patent Document 2: U.S. Pat. No. 6,294,346 specification
Non-Patent Document 1: Michio Tohru, Yoshibumi Nakane, Minoru Komiyama, Yuuji Okazaki, Yoshirou Ohkubo, “ICD-10 Seishin oyobi koudou no syougai-Rinshou kijutu to sindan gaidorain-Shinteiban (ICD-10 mental and behavioral disorder-clinical description and diagnosis guidelines—a newly revised edition)”, Igaku-Shoin, November, 2005, p. 23-49
Non-Patent Document 2: Br. J. Psychiatry., 1988, 172: p. 527-532
Non-Patent Document 3: Biol. Psychiatry., 1993, 33(4): p. 236-246
Non-Patent Document 4: Biol. Psychiatry., 1996, 40(11): p. 1091-1099
Non-Patent Document 5: Brain, 2002, 125: p. 1428-1449
Non-Patent Document 6: Nat. Med., 1998, 11: p. 1313-1317
Non-Patent Document 7: Science, 2003, 301: p. 805-809
Non-Patent Document 8: J. Neurosci. Res., 2002, 69(1): p. 72-79